Associations of Dietary Intake Traits and Aging Indicators With Colorectal Cancer: A Mendelian Randomization Study

Colorectal cancer (CRC) is a major global health burden with an increasing incidence among younger adults. High-glycemic food intake and biological aging have been proposed as potential risk factors for CRC, but their causal relationships and underlying mechanisms remain unclear. We conducted a two-sample Mendelian randomization (MR) study using large-scale genome-wide association study summary data to evaluate the genetic associations of 25 high-glycemic food intake traits and five aging-related indicators, including GrimAge acceleration, intrinsic epigenetic age acceleration, PhenoAge acceleration, Hannum age acceleration, and mitochondrial DNA copy number, with CRC risk. Two-step MR was used to explore potential mediating role of aging indicators. MR analyses showed nominally significant positive associations of intake of sugar added to tea (OR = 1.307, 95% CI: 1.033-1.655, p = 0.026, FDR = 0.216) and doughnut intake (OR = 2.524, 95% CI: 1.317-4.835, p = 0.005, FDR = 0.131) with CRC risk, whereas yogurt intake was nominally associated with lower CRC risk (OR = 0.755, 95% CI: 0.596-0.958, p = 0.020, FDR = 0.216). These food-CRC associations did not survive FDR correction and should therefore be interpreted as suggestive evidence. GrimAge acceleration showed a positive genetic association with CRC risk (OR = 1.102, 95% CI: 1.039-1.169, p = 0.001). Mediation analysis suggested that GrimAge acceleration may partly mediate the association between intake of sugar added to tea and CRC risk, with an estimated mediated proportion of 36.1%. These findings provide genetic evidence suggesting potential links among specific high-glycemic food intake traits, epigenetic aging, and CRC risk; however, mediation finding did not pass strict significance testing and requires validation in larger and independent datasets.